Use of borate-polyol complexes in ophthalmic compositions

ABSTRACT

Water-soluble borate-polyol complexes are useful as buffers and/or antimicrobials in aqueous ophthalmic compositions, including those containing polyvinyl alcohol. These compositions have greater antimicrobial activity than comparable compositions containing typical borate buffers and unexpectedly increase the antimicrobial efficacy of other antimicrobial agents when used in combination. In addition, use of the boratepolyol complexes avoids the incompatibility problem typically associated with the combination of borate buffer and polyvinyl alcohol; therefore, the compositions disclosed herein may also contain polyvinyl alcohol.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 09/597,310, filed Jun. 20, 2000, (now U.S. Pat. No. 6,365,636),which is a continuation of U.S. patent application Ser. No. 09/109,453,filed Jul. 2, 1998, (now U.S. Pat. No. 6,143,799), which is a divisionalof U.S. patent application Ser. No. 08/479,281, filed Jun. 7, 1995, (nowU.S. Pat. No. 5,811,466), which is a divisional of U.S. patentapplication Ser. No. 08/198,427, filed Feb. 22, 1994, (now U.S. Pat. No.5,505,953), which is a continuation-in-part of U.S. patent applicationSer. No. 08/118,833, filed Sep. 7, 1993, (now U.S. Pat. No. 5,342,620),which is a continuation of U.S. patent application Ser. No. 07/879,435,filed May 6, 1992, (now abandoned).

BACKGROUND OF THE INVENTION

This invention relates to the use of borate-polyol complexes inophthalmic compositions. In particular, these complexes are useful asbuffers and/or antimicrobial agents in aqueous ophthalmic compositions,including those ophthalmic compositions containing polyvinyl alcohol.

Ophthalmic compositions are generally formulated to have a pH betweenabout 4.0 and 8.0. To achieve a pH in this range and to maintain the pHfor optimal stability during the shelf life of the composition, a bufferis often included. Borate is the buffer of choice for use in ophthalmiccompositions, since it has some inherent antimicrobial activity andoften enhances the activity of antimicrobials; however, when polyvinylalcohol (PVA) is also an ingredient in the composition, borate and PVAform a water-insoluble complex which precipitates out of solution andacts as an irritant in the eye. This incompatibility of borate and PVAin contact lens solutions is well-known, and has been discussed, forexample, in an article by P. L. Rakow in Contact Lens Forum, (June1988), pages 41-46. Moreover, borate buffer cannot be effectively usedbelow pH 7.0 due to its low buffering capacity to lower pH.

Since borate is incompatible with PVA, ophthalmic compositionscontaining PVA are generally buffered with acetate, phosphate or otherbuffers. There are disadvantages to using these alternative buffers: forexample, acetate is a weak buffer (pK_(a) of about 4.5), so a relativelylarge amount is needed; on the other hand, phosphate is a good bufferbut, when used in concentrations generally found in ophthalmicformulations, it reduces the antimicrobial activity of preservatives.

It is well known that small organic compounds, such as benzalkoniumchloride (BAC), chlorhexidine, thimerosal have excellent antimicrobialactivity; however, it is now known that these small organicantimicrobials are often toxic to the sensitive tissues of the eye andcan accumulate in contact lenses, particularly soft, hydrophilic contactlenses. More recently, polymeric antimicrobials such as Polyquad®(polyquaternium-1) and Dymed® (polyhexamethylene biguanide) have beenused in contact lens care products as disinfectants and preservatives.While these polymeric antimicrobials exhibit a broad spectrum ofantimicrobial activity, they generally have relatively weak antifungalactivity, especially against Aspergillus niger and Aspergillusfumigatus.

A need therefore exists for ophthalmic compositions which have anoptimal pH for stability and efficacy, but whose antimicrobial efficacyis not compromised.

SUMMARY OF THE INVENTION

This invention provides such ophthalmic compositions. The ophthalmiccompositions of the present invention comprise borate-polyol complexeswhich have surprisingly been found to have increased antimicrobialactivity as compared to boric acid or its salts, particularly withrespect to organisms such as A. niger. Moreover, these complexesunexpectedly increase the antimicrobial efficacy of other antimicrobialagents when used in combination.

The borate-polyol complexes are formed by mixing boric acid and/or itssalts with polyols, such as mannitol, glycerin or propylene glycol, inan aqueous solution. The resultant solution may then be used as a bufferand/or antimicrobial agent in aqueous ophthalmic compositions, evenwhere such compositions also contain PVA. The borate-polyol complexes ofthe present invention are also useful in unpreserved saline solutions.

The borate-polyol complexes of the present invention are particularlyuseful as adjunctive disinfecting agents in contact lens disinfectingsolutions containing monomeric quaternary ammonium compounds (e.g.,benzalkonium chloride) or biguanides (e.g., chlorhexidine) or polymericantimicrobials, such as polymeric quaternary ammonium compounds (e.g.,Polyquad®, Alcon Laboratories, Inc., Fort Worth, Tex.) or polymericbiguanides (e.g., Dymed®, Bausch & Lomb, Rochester, N.Y.).

The compositions of the present invention may optionally contain PVA;such compositions are particularly useful in contact lens care productswhich are targeted for wearers of rigid gas-permeable contact lenses(RGPs), who often complain of discomfort. PVA is a viscosity enhancerand is used extensively in all types of RGP products in order to improvethe comfort and wearing time of RGPs. PVA is also extensively used as aviscosity enhancer for pharmaceutical ophthalmic compositions such aseye drops, gels or ocular inserts.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “borate” shall refer to boric acid, salts ofboric acid and other pharmaceutically acceptable borates, orcombinations thereof. Most suitable are: boric acid, sodium borate,potassium borate, calcium borate, magnesium borate, manganese borate,and other such borate salts.

As used herein, and unless otherwise indicated, the term “polyol” shallrefer to any compound having at least two adjacent -OH groups which arenot in trans configuration relative to each other. The polyols can belinear or circular, substituted or unsubstituted, or mixtures thereof,so long as the resultant complex is water-soluble and pharmaceuticallyacceptable. Such compounds include sugars, sugar alcohols, sugar acidsand uronic acids. Preferred polyols are sugars, sugar alcohols and sugaracids, including, but not limited to: mannitol, glycerin, propyleneglycol and sorbitol. Especially preferred polyols are mannitol andglycerin; most preferred is mannitol.

The water-soluble borate-polyol complexes of the present invention maybe formed by mixing borate with the polyol(s) of choice in an aqueoussolution. These complexes can be used in conjunction with other knownpreservatives and disinfectants to meet preservative efficacy anddisinfection standards. In such compositions, the molar ratio of borateto polyol is generally between about 1:0.1 and about 1:10, and ispreferably between about 1:0.25 and about 1:2.5.

The borate-polyol complexes may also be used in unpreserved salines tomeet preservative efficacy standards. In these unpreserved salines, themolar ratio of borate to polyol is generally between about 1:0.1 andabout 1:1, and is especially between about 1:0.25 and about 1:0.75. Someborate-polyol complexes, such as potassium borotartrate, arecommercially available.

The borate-polyol complexes are utilized in the compositions of thepresent invention in an amount between about 0.5 to about 6.0 percent byweight (wt %), preferably between about 1.0 to about 2.5 wt %. Theoptimum amount, however, will depend upon the complexity of the product,since potential interactions may occur with the other components of acomposition. Such optimum amount can be readily determined by oneskilled in the formulatory arts.

The compositions of the present invention useful with RGPs orcompositions such as eye drops, gels or ocular inserts will preferablyalso contain PVA or other viscosity-enhancing polymers, such ascellulosic polymers or carboxy vinyl polymers. PVA is available in anumber of grades, each differing in degree of polymerization, percent ofhydrolysis, and residual acetate content. Such differences affect thephysical and chemical behavior of the different grades. PVA can bedivided into two broad categories, i.e., completely hydrolyzed andpartially hydrolyzed. Those containing 4% residual acetate content orless are referred to as completely hydrolyzed. Partially hydrolyzedgrades usually contain 20% or more residual acetate. The molecularweight of PVA's vary from 20,000 to 200,000. In general, PVA used inophthalmic products has an average molecular weight in the range of30,000 to 100,000 with 11% to 15% residual acetate. Compositions of thepresent invention generally contain such types of PVA at a concentrationless than about 10.0 wt %, preferably between about 0.1 and about 1.4 wt% and most preferably at a concentration of about 0.75 wt %.

EXAMPLE 1

The water-soluble borate-polyol complexes of the present invention maybe prepared as illustrated below.

FORMULATION (% weight/volume) INGREDIENT A B C D E F G H Boric acid 0.350.35 0.35 0.35 0.35 0.35 0.35 0.35 Sodium 0.11 0.11 0.11 0.11 0.11 0.110.11 0.11 borate Mannitol 0.5 1.0 1.5 2.0 — — — — Glycerin — — — — 0.51.0 1.5 2.0 Na₂EDTA 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Purified q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. water HCl/NaOH pH 7.4 pH 7.4 pH 7.4 pH 7.4pH 7.4 pH 7.4 pH 7.4 pH 7.4 Polyquad ® 0.001 + 0.001 + 0.001 + 0.001 +0.001 + 0.001 + 0.001 + 0.001 + 10% xs 10% xs 10% xs 10% xs 10% xs 10%xs 10% xs 10% xs

Preparation:

Formulations A-H were prepared as follows. Tubular, labeled andcalibrated 150 milliliter (mL) beakers were each filled with about 90 mLof purified water. Boric acid, sodium borate and mannitol or glycerinwere then added and dissolved by stirring the solution for about 25minutes. At this time, disodium EDTA (ethylene diamine tetraacetic acid)was added with stirring. Purified water was added to bring the solutionsalmost to 100% (100 mL), pH was adjusted to approximately 7.4 and theosmolality was measured. Polyquad® was then added and the volume broughtto 100% by the addition of purified water. pH was again measured andadjusted, if necessary, and the osmolality was measured again.

It is not always necessary to have an isotonic solution; however, ifthere is a need to have an isotonic solution, the osmolality can beadjusted by incorporating polyol with OH groups in trans position,sodium chloride, potassium chloride, calcium chloride or otherosmolality building agents which are generally acceptable in ophthalmicformulations and known to those skilled in the art.

EXAMPLE 2

Aqueous ophthalmic compositions of the present invention may be preparedusing the formulations illustrated below.

FORMULATION (percent by weight) INGREDIENT 1 2 3 4 5 6 7 8 9 PVA 0.751.4 0.75 0.75 0.75 0.75 0.75 0.75 0.75 Hydroxyethyl cellulose — — 0.750.28 0.28 0.28 0.28 0.75 0.75 (HEC) Mannitol 2.0 2.0 2.0 2.0 2.0 2.0 0.52.0 2.0 Boric acid 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Sodiumborate 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 Edetate disodium 0.10.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Sodium chloride 0.09 0.09 0.09 0.09 0.450.09 0.09 0.09 0.09 Polyquad ® 0.001 0.001 0.001 0.001 0.001 0.001 0.001— — Sucrose — — — — — 2.5 — 2.5 2.5 Polyhexamethylene — — — — — — —0.0005 — biguanide BAC — — — — — — — — 0.004

Preparation:

Formulations 1-9 were prepared as follows. A first solution (Solution A)was prepared by adding 500 mL of warm purified water to a calibrated twoliter aspirator bottle equipped with a magnetic stirrer. PVA andhydroxyethyl cellulose were then added to Solution A and the contentsdispersed by stirring. After dispersal of the polymers, a filterassembly was attached to the aspirator bottle (142 mm Millipore filterholder with 0.2 i filter), and this whole apparatus autoclaved at 121°C. for 30 minutes. Solution A with the filter assembly attached was thenallowed to cool to room temperature with stirring. A second solution(Solution B), was prepared in a 500 mL beaker containing 300 mL ofpurified water by adding boric acid, sodium borate and mannitol anddissolving the contents by stirring for 25 minutes. Edetate disodium,sodium chloride, preservatives and other osmolality-building agents, asnecessary, were added to Solution B and the contents dissolved withstirring. Solution B was then sterile filtered into the aspirator bottlecontaining Solution A. The pH of the resultant solution was thenadjusted and the volume brought to 100% by sterile filtering purifiedwater.

EXAMPLE 3

The following ophthalmic compositions of the present invention may alsobe prepared using the procedure detailed in Example 2.

FORMULATION (percent by weight) INGREDIENT 10 11 12 13 14 15 16 17 18 19PVA 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 Naphazolene HCl 0.1 0.1 — —— — — — — — Sodium — — — 10.0 — — — — — — sulfacetamide Fluorometholone— — — — 0.1 — — — — — Gentamycin sulfate — — — — — 0.4 — — — —Levobunolol HCl — — 0.5 — — — — — — — Mydrysone — — — — — — 1.0 — — —Pilocarpine nitrate — — — — — — — 1.0 1.0 1.0 Sodium — — 0.4 — — — — — —— metabisulfite Mannitol 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 4.0 0.5 Boricacid 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.5 Sodium borate 0.110.11 0.11 0.11 0.11 0.11 0.11 0.11 — — Sodium chloride 0.45 0.45 0.45 —0.45 0.45 0.45 0.45 — — Edetate disodium 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.10.1 0.1 BAC 0.004 — — — — — — — — — Polyquad ® — 0.001 0.001 0.001 0.0010.001 0.001 0.001 0.001 0.001

EXAMPLE 4

The following is a typical wetting and soaking composition of thepresent invention for use with RGPs.

INGREDIENT AMOUNT (wt %) PVA 0.75 HEC 0.38 Boric acid 0.35 Sodium borate0.11 Mannitol 2.0 Potassium chloride 0.038 Magnesium chloride 0.02Calcium chloride 0.0154 Sodium chloride 0.09 Polysorbate 80 0.005Polyquad ® 0.001 NaOH and/or HCl pH 7.4 Purified water q.s.

Preparation:

In a suitable container containing approximately 30% of the final volumeof purified water, PVA and HEC were added and dispersed. This solutionwas then autoclaved. The solution was allowed to cool to roomtemperature with stirring. In a separate container, containingapproximately 50% of the final volume of purified water, boric acid andsodium borate were added, and dissolved, followed by mannitol. Thissecond solution was then stirred for about 30 minutes, then potassimchloride, calcium chloride, magnesium chloride, sodium chloride,polysorbate 80 and Polyquad® were added, with stirring. The secondsolution was then added to the first solution via a 0.2 i filter. Last,the pH was adjusted to 7.4 and the volume brought to 100% with purifiedwater.

EXAMPLE 5

The following is a typical daily cleaner composition of the presentinvention for use with RGPs and may be prepared in a manner similar tothat detailed in Example 4.

INGREDIENT AMOUNT (wt %) Nylon 1111 2.50 Dextran 70 6.0 Sodium borate0.25 Boric acid 0.50 Miracare ® 2MCA 0.50 PDMA-1 0.15 Propylene glycol10.0 Polyquad ® 0.0055 EDTA 0.10 Mannitol 1.20 NaOH and/or HCl pH 7.4Purified water q.s.

EXAMPLE 6

The following is a typical wetting and soaking composition of thepresent invention which may be prepared in a manner similar to thatdetailed in Example 4.

INGREDIENT AMOUNT (wt %) Hydroxypropyl 0.72 methylcellulose (Methocel ®E4M) Mannitol 1.0 Sodium borate 0.11 Boric acid 0.35 Sodium chloride0.19 Polyquad ® 0.0011 EDTA 0.10 NaOH and/or HCl pH 7.4 Purified waterq.s.

EXAMPLE 7

The following is a typical comfort drop composition of the presentinvention which may be prepared in a manner similar to that detailed inExample 4.

INGREDIENT AMOUNT (w/v %) PVA 0.75 HEC 0.28 Mannitol 2.0 Sodium borate0.11 Boric acid 0.35 Sodium chloride 0.152 Polyquad ® 0.00082 EDTA 0.10NaOH and/or HCl pH 7.4 Purified water q.s.

EXAMPLE 8

The following is a typical RGP cleaner composition of the presentinvention which may be prepared in a manner similar to that detailed inExample 4.

INGREDIENT AMOUNT (wt %) French Naturelle ® ES (Nylon 2.5 11)Hydroxyethyl cellulose 0.4 Sodium borate, decahydrate 0.25 Boric acid0.50 Mannitol 3.5 Miracare ® 2MCA) 0.50 Isopropyl alcohol (v/v) 10.0NaOH and/or HCl q.s. 7.4 Purified water q.s.

EXAMPLE 9

The following is a typical RGP wetting and/or soaking composition of thepresent invention, which may be prepared in a manner similar to thatdetailed in Example 4.

INGREDIENT AMOUNT (wt %) Methocel ® E4M 0.85 Mannitol 2.00 Sodium borate0.11 Boric acid 0.35 Sodium chloride 0.19 Disodium edetate 0.1Polyquad ® 0.001 NaOH and/or HCl pH 7.4 Purified water q.s.

EXAMPLE 10

The following study compared the antimicrobial preservative efficacy oftwo wetting, soaking and disinfecting solutions: one containingphosphate buffer (Formulation A); and the other containing aborate-polyol complex of the present invention (Formulation B).

Formulations A and B are shown in the following table.

FORMULATION (wt %) INGREDIENT A B PVA 0.75 0.75 HEC 0.5 0.5 Sodiumphosphate 0.67 — Sodium biophosphate 0.017 — Boric acid — 0.35 Sodiumborate — 0.11 Mannitol — 2.0 Disodium edetate 0.1 0.1 Sodium chloride0.458 0.153 Polysorbate 80 0.005 0.005 Benzalkonium chloride 0.01 0.01Purified water q.s. q.s.

Formulations A and B were tested against FDA challenge organisms. Thelog reductions after 1 hour are tabulated below:

FORMULATION (log reduction) TEST ORGANISM A B A. niger 2.1 4.4 B.albicans 4.0 5.3 P. aeruginosa 5.3 5.3 S. aureus 5.5 5.2 E. coli 5.5 5.5

The results shown above indicate that Formulation B (containingborate-polyol complex) has a broader spectrum of activity thanFormulation A (containing phosphate buffer), and has greater activityagainst certain organisms, such as A. niger.

EXAMPLE 11

The following study compared the antimicrobial preservative efficacy oftwo unpreserved saline solutions identical except that one contained aborate-polyol complex of the present invention (Formulation C) and theother contained the conventional borate buffer (Formulation D).

An organism challenge approach based on the British Pharmacopoeia (“BP”)1988 Test for Efficacy of Preservatives in Pharmaceutical Products wasused to evaluate the antimicrobial preservative efficacy of FormulationsC and D. Formulation samples were inoculated with known levels of A.niger and sampled at predetermined intervals to determine if the systemwas capable of killing or inhibiting the propagation of organismsintroduced into the products.

Formulations C and D are shown in the following table.

FORMULATION (wt %) INGREDIENT C D Boric acid 1.0 1.0 Sodium borate 0.20.2 Mannitol 1.5 — Sodium chloride — 0.3 Disodium edetate 0.1 0.1 NaOHand/or HCl pH 7.4 pH 7.4 Purified water q.s. q.s.

The results indicated that there was a 3.1 log reduction of A. nigerwith Formulation C and only 1.2 log reduction with Formulation D after 7days. Formulation C met the BP standards for preservative efficacyagainst A. niger, while Formulation D failed to meet the BP standards.

EXAMPLE 12

The following study compared the antimicrobial preservative efficacy oftwo disinfecting solutions identical except that one contained aborate-polyol complex of the present invention (Formulation E) and theother contained the conventional borate buffer (Formulation F).

An organism challenge approach based on the BP 1988 Test for Efficacy ofPreservatives in Pharmaceutical Products was used to evaluate theantimicrobial preservative efficacy of Formulations E and F. Formulationsamples were inoculated with known levels of A. niger and sampled atpredetermined intervals to determine if the system was capable ofkilling or inhibiting the propagation of organisms introduced into theproducts.

Formulations E and F are shown in the following table.

FORMULATION (wt %) INGREDIENT E F Boric acid 0.3 0.35 Sodium borate 0.110.11 Mannitol 0.85 — Sodium citrate 0.56 0.56 Citric acid 0.021 0.21Sodium chloride 0.48 0.48 Pluronic P103 0.5 0.5 Disodium edetate 0.050.05 Polyquad ® 0.001 0.001 NaOH and/or HCl pH 7.0 pH 7.0 Purified waterq.s. q.s.

The results indicate that there was a 2.1 log reduction of A. niger withFormulation E and only 1.1 log reduction with Formulation F after 7days. Formulation E met the BP standards for preservative efficacyagainst A. niger, while Formulation F failed to meet the BP standards.

The invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

What is claimed is:
 1. An aqueous ophthalmic composition comprising: 0.5to 6.0 wt. % of a water soluble borate-polyol complex to enhance theantimicrobial activity of the composition, and water, said complexcontaining borate and polyol in a molar ratio of 1:0.1 to 1:10.
 2. Anaqueous ophthalmic composition according to claim 1, wherein theborate-polyol complex comprises a borate selected from the groupconsisting of boric acid, sodium borate, potassium borate, calciumborate, magnesium borate and manganese borate.
 3. An aqueous ophthalmiccomposition according to claim 1, wherein the polyol is selected fromthe group consisting of mannitol, glycerin, propylene glycol andsorbitol.
 4. An aqueous ophthalmic composition according to claim 3,wherein the polyol comprises mannitol.
 5. An aqueous ophthalmiccomposition according to claim 3, wherein the polyol comprises glycerin.6. An aqueous ophthalmic composition according to claim 3, wherein thepolyol comprises propylene glycol.
 7. An aqueous ophthalmic compositionaccording to claim 3, wherein the polyol comprises sorbitol.
 8. Anaqueous ophthalmic composition according to any one of claims 1 to 7,wherein the borate-polyol complex is included in the composition at aconcentration of 1.0 to 2.5 wt. %.
 9. An aqueous ophthalmic compositionaccording to any one of claims 1 to 7, wherein the molar ratio of borateto polyol is 1:0.25 to 1:2.5.
 10. An aqueous ophthalmic compositionaccording to any one of claims 1 to 7, wherein the molar ratio of borateto polyol is 1:0.1 to 1:1.
 11. An aqueous ophthalmic compositionaccording to any one of claims 1 to 7, wherein the molar ratio of borateto polyol is 1:0.25 to 1:0.75.
 12. An aqueous ophthalmic compositionaccording to any one of claims 1 to 7, wherein the borate-polyol complexis included in the composition at a concentration of 1.0 to 2.5 wt. %,and the molar ratio of borate to polyol is 1:0.25 to 1:2.5.
 13. Anaqueous ophthalmic composition according to any one of claims 1 to 7,wherein the borate-polyol complex comprises boric acid.
 14. An aqueousophthalmic composition according to claim 13, wherein the borate-polyolcomplex is included in the composition at a concentration of 1.0 to 2.5wt. %, and the molar ratio of borate to polyol is 1:0.1 to 1:1.
 15. Anaqueous ophthalmic composition according to any one of the claims 1 to7, wherein the borate-polyol complex comprises boric acid and sodiumborate.
 16. An aqueous ophthalmic composition according to claim 15,wherein the borate-polyol complex is included in the composition at aconcentration of 1.0 to 2.5 wt. %, and the molar ratio of borate topolyol is 1:0.1 to 1:1.
 17. An aqueous ophthalmic composition accordingto any one of claims 1 to 7, wherein the composition further comprises apreservative effective amount of an ophthalmically acceptableantimicrobial agent.
 18. An aqueous ophthalmic composition according toclaim 17, wherein the antimicrobial agent comprises polyquaternium-1.19. An aqueous ophthalmic composition according to any one of claims 1to 7, wherein the composition does not contain an ophthalmicallyacceptable antimicrobial agent.
 20. An aqueous ophthalmic compositionaccording to claim 8, wherein the composition is unpreserved.
 21. Anaqueous, unpreserved ophthalmic solution comprising an amount of a watersoluble borate-polyol complex effective to enhance the antimicrobialactivity of the solution.
 22. An aqueous ophthalmic solution comprising:0.5 to 6.0 wt. % of a water soluble borate-polyol complex to enhance theantimicrobial activity of the solution, and water, said borate-polyolcomplex comprising borate and glycerin in a molar ratio of 1:0.1 to1:10.
 23. An aqueous ophthalmic solution according to claim 22, whereinthe solution further comprises an effective amount of a viscosityenhancing polymer.
 24. An aqueous ophthalmic solution according to claim23, wherein the viscosity-enhancing polymer comprises a cellulosicpolymer.
 25. An aqueous ophthalmic solution according to claim 24,wherein the cellulosic polymer comprises hydroxypropyl methylcellulose.26. An aqueous ophthalmic solution according to any one of claims 22 to25, wherein the solution further comprises a preservative effectiveamount of an ophthalmically acceptable antimicrobial agent.
 27. Anaqueous ophthalmic solution according to claim 26, wherein theophthalmically acceptable antimicrobial agent comprisespolyquaternium-1.
 28. An aqueous ophthalmic solution according to anyone of claims 22 to 25, wherein the solution does not contain anophthalmically acceptable antimicrobial agent.
 29. An aqueous ophthalmicsolution according to any one of claims 22 to 25, wherein the solutioncontains the borate-polyol complex in an amount of 1.0 to 2.5 wt. %. 30.An aqueous ophthalmic solution according to claim 29, wherein the molarratio of borate to polyol is 1:0.1 to 1:1.
 31. An aqueous ophthalmicsolution according to claim 29, wherein the molar ratio of borate topolyol is 1:0.25 to 1:2.5.
 32. An aqueous ophthalmic solution accordingto claim 29, wherein the solution is unpreserved.
 33. An aqueousophthalmic solution comprising: 0.5 to 6.0 wt. % of a water solubleborate-polyol complex to enhance the antimicrobial activity of thesolution, and water, wherein the borate-polyol complex comprises borate,propylene glycol and sorbitol and the molar ratio of borate to polyol is1:0.1 to 1:10.
 34. An aqueous ophthalmic solution according to claim 33,wherein the solution further comprises an effective amount of aviscosity-enhancing polymer.
 35. An aqueous ophthalmic solutionaccording to claim 34, wherein the viscosity-enhancing polymer comprisesa cellulosic polymer.
 36. An aqueous ophthalmic solution according toclaim 35, wherein the cellulosic polymer comprises hydroxypropylmethylcellulose.
 37. An aqueous ophthalmic solution according to any ofclaims 33 to 36, wherein the solution further comprises a preservativeeffective amount of an ophthalmically acceptable antimicrobial agent.38. An aqueous ophthalmic solution according to claim 37, wherein theophthalmically acceptable antimicrobial agent comprisespolyquaternium-1.
 39. An aqueous ophthalmic solution according to anyone of claims 33 to 36, wherein the solution does not contain anophthalmically acceptable antimicrobial agent.
 40. An aqueous ophthalmicsolution according to any one of claims 33 to 36, wherein the solutioncontains the borate-polyol complex in an amount of 1.0 to 2.5 wt. %. 41.An aqueous ophthalmic solution according to claim 40, wherein the molarratio of borate to polyol is 1:0.1 to 1:1.
 42. An aqueous ophthalmiccomposition according to claim 40, wherein the molar ratio of borate topolyol is 1:0.25 to 1:2.5.
 43. An aqueous ophthalmic solution accordingto claim 40, wherein the solution is unpreserved.
 44. An aqueousophthalmic solution comprising: a viscosity-enhancing amount ofhydroxypropyl methylcellulose; 1.0 to 2.5 wt. % of a borate-polyolcomplex, said complex comprising boric acid and glycerin in a molarratio of 1:0.1 to 1:1; 0.001 w/v % of polyquaternium-1; and water. 45.An aqueous, unpreserved ophthalmic solution comprising: aviscosity-enhancing effective amount of hydroxypropyl methylcellulose;1.0 to 2.5 wt. % of a borate-polyol complex comprising boric acid,propylene glycol and sorbitol, wherein the molar ratio of borate topolyol is 1:0.1 to 1:1; and water.